Abstract Fusobacterium nucleatum (F. nucleatum) is a key microbial driver of colorectal cancer (CRC) progression. Here, we identified an intercellular signaling axis through which F. nucleatum remodels the immune microenvironment. Analysis of 54 clinical CRC specimens revealed that high intratumoral F. nucleatum load correlated significantly with PD-L1 upregulation in tumor-associated macrophages, diminished CD8⁺ T-cell cytotoxicity, and poor patient prognosis. Mechanistically, F. nucleatum infection activated NF-κB signaling in CRC cells to induce the transcription of the long non-coding RNA MANCR, which was selectively packaged into exosomes via the ESCRT-III/Alix complex and transferred to macrophages. In recipient macrophages, exosomal MANCR interacted with hnRNP U to increase PD-L1 mRNA stability, leading to sustained PD-L1 surface expression. In humanized mouse models, F. nucleatum exposure inhibited CD8⁺ T-cell infiltration and suppressed granzyme B activity, thereby compromising antitumor immunity and facilitating tumor proliferation and metastasis. These findings demonstrate that F. nucleatum exploits a tumor-derived exosomal lncRNA network to remotely manipulate macrophage plasticity. Targeting the F. nucleatum/MANCR/PD-L1 axis may therefore represent a viable strategy to overcome immune resistance in the CRC microenvironment.
Han et al. (Wed,) studied this question.